In this revised R29 application, we plan to characterize pancreatic reg I. Preliminary experiments have shown that reg I expression correlates with insulin gene expression, islet proliferation and even beta-cell function. The human protein is mitogenic to beta- and ductal cells, indicating that its mechanism of action is probably through induction of proliferation. A biologically active fragment has been isolated. Experiments in this grant are focused on the mechanism of rat reg I action. Our Specific Aims are: (1) Isolate rat reg I protein and determine mitogenesis on pancreatic-derived cells. (2) Perform bindings studies of rat reg I protein with pancreatic target cells. (3) Determine whether pancreatic reg I is critical for normal islet function. Research design and methods: Rat reg I has been cloned into an expression vector and recombinant protein produced. Mitogenesis of the protein and the biologically active fragment to pancreatic-derived cells will be assayed by thymidine and BrdU incorporation. Binding studies to pancreatic target cells will be performed using radiolabelled protein. To characterize the role of reg I in beta-cell function, a rat model of acinar cell loss has been developed. Progressive loss of pancreatic reg I will be correlated with impaired glucose tolerance. Candidate: The candidate is a gastrointestinal surgeon interested in basic pancreatic physiology, and has proven ability as an independent investigator. Environment: Research will be carried out in the laboratory of the candidate. A formal collaboration has been established with the Diabetes Research and Training Center, which contains molecular, antibody and receptor analysis Research facilities.